Parathyroid hormone (PTH), acting through the PTH receptor (PTHR1), expressed in bone and kidney, plays a vital role in maintaining proper blood levels of calcium and phosphate, and also contributes to the regulation of bone growth and remodeling. PTHrP, acting through the same PTHR1, regulates the development of the skeleton and other tissues. Drugs that target the PTHR1 are of interest because they could potentially be used to treat human diseases, such as osteoporosis and hypoparathyroidism (HPT). Yet PTH(1-34) is the only FDA-approved PTH-based therapy. It is thus used to treat osteoporosis, and, while effective, must be injected once a day. The proposed studies will define the molecular mechanisms by which PTH ligands bind to and activate the PTHR1. They will generate new types of PTH analogs, including signaling selective analogs and novel long-acting ligands that are structurally more stable or have adducts that impair renal clearance, and will assess these analogs for binding to the PTHR1 in vitro, and for actions in animals. Also explored will be new non-peptidic, small-molecule ligands for the PTHR1. Selected ligands will be evaluated in a mouse model of HPT (PTH-null mice) for their capacity to normalize blood calcium. New long-acting PTH analogs will also be tested for their capacities to stimulate bone formation and improve strength when injected into mice at low-frequency intervals, such as once-weekly, and in a dual-therapy mode with the bone-resorption inhibitor, OPG-FC.